Clofibric acid induces hepatic CYP 2B1/2 via constitutive androstane receptor not via peroxisome proliferator activated receptor alpha in rat.

Peroxisome proliferator activated receptor α (PPARα) ligands, fibrates used to control hyperlipidemia. We demonstrated CYP2B induction by clofibric acid (CFA) however, the mechanism was not clear. In this study, HepG2 cells transfected with expression plasmid of mouse constitutive androstane receptor (CAR) or PPARα were treated with CFA, phenobarbital (PB) or TCPOBOP. Luciferase assays showed that CFA increased CYP2B1 transcription to the same level as PB, or TCPOBOP in HepG2 transfected with mouse CAR But failed to induce it in PPARα transfected cells. CYP2B expressions were increased with PB or CFA in Wistar female rats (having normal levels of CAR) but not in Wistar Kyoto female rats (having low levels of CAR). The induction of CYP2B by PB or CFA was comparable to nuclear CAR levels. CAR nuclear translocation was induced by CFA in both rat strains. This indicates that fibrates can activate CAR and that fibrates-insulin sensitization effect may occur through CAR, while hypolipidemic effect may operate through PPARα.

Conservative treatment of L-asparaginase-associated lipid abnormalities in children with acute lymphoblastic leukemia.

OBJECTIVE: To determine the incidence and clinical consequences of asparaginase-associated lipid abnormalities in children with acute lymphoblastic leukemia (ALL). METHODS: Sixty-five newly diagnosed children and adolescents aged 0.4-21 years with ALL or lymphoblastic lymphoma were retrospectively evaluated for lipid abnormalities. They were treated according to the ALLIC-BFM 2002 protocol between 2002 and 2005. Fasting cholesterol levels were measured in all patients and triglycerides (TG) in 42/65 patients. RESULTS: Prior to treatment, mean cholesterol level was 149 +/- 50 mg/dl, and increased to maximal level 274 +/- 124 mg/dl during treatment. Mean TG level during treatment was 459 +/- 526 mg/dl (range 54-3,009). Twelve patients (28%) had TG levels <200 mg/dl, 18 (43%) had 200-400 mg/dl, 3 (7%) had 400-600 mg/dl, 4 (10%) between 600 and 1,000 mg/dl, and 5 (12%) patients had >1,000 mg/dl. No association was found between TG levels and age or gender. One of the 12 patients with TG >400 mg/dl developed left saggital sinus thrombosis and left frontal lobe infarct. TG level at the time of the event was 2,640 mg/dl. None of the five patients with TG levels >1,000 mg/dl developed pancreatitis. Children with TG levels between 400 and 600 mg/dl were treated by fasting. Fibrates and heparin were added to those with levels >600 mg/dl. Lipid abnormalities normalized in all children upon completion of asparaginase treatment. CONCLUSIONS: Abnormalities of lipid profile in children with ALL during asparaginase therapy are relatively common. We recommend measuring TG before and during asparaginase treatment. Initiation of conservative treatment could prevent further increase of TG and decrease the risk of potential complications.

[Efficacy and safety of etofibrate in patients with non-proliferative diabetic retinopathy]. / Wirksamkeit und Sicherheit von Etofibrat bei Patienten mit nicht proliferativer diabetischer Retinopathie.

INTRODUCTION: Diabetic retinopathy is the leading cause of vision loss or blindeness in working-age adults in the developed and developing countries. No curative treatments are available for diabetic retinopathy and the most common symptomatic treatment, laser photocoagulation, provides only partial and temporary relief from the progressive vascular damage caused by this disease. Etofibrate (Lipo-Merz) is an orally-administered treatment for lipid disorders that combines fibrate and nicotinic acid in a slow-release formulation. PATIENTS AND METHODS: This report describes the results of a double-blind, randomised, placebo-controlled study, performed to evaluate the efficacy and safety of etofibrat in patients with type 2 diabetes mellitus and concomitant diabetic retinopathy. They received either placebo or 1000 mg/day etofibrate for up to 12 months. Efficacy analyses were based on visual acuity assessment and blinded expert ratings of ocular fundus pathology, as well as laboratory analyses of serum lipid parameters. RESULTS: The evaluable population comprised 296 patients, 148 in each treatment group, of whom 89% completed the study and 73% completed according to protocol. After 12 months of treatment, a significantly larger population of etofibrate-treated patients than placebo-treated patients showed improvements in ocular pathology (46% versus 32%, respectively, p < 0.001); similar findings were already apparent after 6 months of treatment (43% versus 31%, respectively p < 0.001). Etofibrate treatment also produced significant improvements in total cholesterol, LDL-cholesterol and HDL-cholesterol in comparison to the placebo treatment group. Safety evaluations (adverse events, laboratory parameters) did not reveal any clinically significant adverse effects of etofibrate in comparison to placebo. CONCLUSION: Etofibrate provides a safe and effective treatment for ocular pathology resulting from type 2 diabetes mellitus.

Etofibrate enhances 123I-LDL-binding in human liver.

Etofibrate, a combination of fibric and nicotinic acid, is successfully used for the treatment of type IIb and IV hyperlipidemia. While an up-regulation of specific low density lipoproteins (LDL) binding sites in human platelets has been demonstrated, action on LDL-binding to the liver in patients and kinetic studies rare. This study aimed to investigate the influence of twice 500mg etofibrate daily given for 6 weeks on the in vivo binding of autologous LDL to the liver in 11 patients, 6 males, 5 females; aged 37-57 years, suffering from mixed hyperlipidemia. Etofibrate enhanced in vivo liver uptake of (123)I-LDL by 16.1% at mean, shortened plasma decay of LDL and improved lipid profile: serum total cholesterol was lowered by 14.9%, LDL-cholesterol was lowered by 22.2% and high-density lipoprotein (HDL)- cholesterol was increased by 10.9%. These findings are documenting a beneficial effect of the drug at the LDL liver receptor level in vivo.

Efficacy of rosuvastatin (5 mg and 10 mg) twice a week in patients intolerant to daily statins.

The aim of this study was to evaluate the efficacy of rosuvastatin twice weekly in 40 patients intolerant to daily statins. Rosuvastatin twice weekly alone or added to other lipid-lowering medications decreased total cholesterol by 19%, low-density lipoprotein cholesterol by 26%, and triglycerides by 14% (p<0.01 for all). High-density lipoprotein cholesterol did not change. Eight of the 40 patients (20%) discontinued twice-weekly rosuvastatin treatment because of muscle-related symptoms, during an average of 8 weeks of treatment. In conclusion, rosuvastatin twice weekly reduced total cholesterol, low-density lipoprotein cholesterol, and triglycerides and was well tolerated, but determining long-term tolerability requires more prolonged treatment.

Plasma PCSK9 levels are significantly modified by statins and fibrates in humans.

BACKGROUND: Proprotein convertase subtilisin kexin-like 9 (PCSK9) is a secreted glycoprotein that is transcriptionally regulated by cholesterol status. It modulates levels of circulating low density lipoprotein cholesterol (LDLC) by negatively regulating low density lipoprotein receptor (LDLR) levels. PCSK9 variants that result in 'gain of function' have been linked to autosomal dominant hypercholesterolemia, while significant protection from coronary artery disease has been documented in individuals who carry 'loss of function' PCSK9 variants. PCSK9 circulates in human plasma, and we previously reported that plasma PCSK9 is positively correlated with total cholesterol and LDLC in men. RESULTS: Herein, we report the effects of two lipid-modulating therapies, namely statins and fibrates, on PCSK9 plasma levels in human subjects. We also document their effects on endogenous PCSK9 and LDLR expression in a human hepatocyte cell line, HepG2, using immunoprecipitation and immunoblot analyses. Changes in plasma PCSK9 following fenofibrate or gemfibrozil treatments (fibric acid derivatives) were inversely correlated with changes in LDLC levels (r = -0.558, p = 0.013). Atorvastatin administration (HMGCoA reductase inhibitor) significantly increased plasma PCSK9 (7.40%, p = 0.033) and these changes were inversely correlated with changes in LDLC levels (r = -0.393, p = 0.012). Immunoblot analyses of endogenous PCSK9 and LDLR expression by HepG2 cells in response to statins and fibrates showed that LDLR is more upregulated than PCSK9 by simvastatin (2.6x vs 1.5x, respectively at 10 muM), while fenofibrate did not induce changes in either. CONCLUSION: These results suggest that in vivo (1) statins directly increase PCSK9 expression while (2) fibrates affect PCSK9 expression indirectly through its modulation of cholesterol levels and (3) that these therapies could be improved by combination with a PCSK9 inhibitor, constituting a novel hypercholesterolemic therapy, since PCSK9 was significantly upregulated by both treatments.

Colchicine: serious interactions.

(1) Renal failure, either pre-existing or induced by a nephrotoxic drug, increases the risk of adverse effects in patients taking colchicine; (2) Combining colchicines with a macrolide (except for spiramycin) carries a risk of life-threatening pancytopenia; (3) Ciclosporin co-administration can aggravate the neuromuscular adverse effects of colchicine; (4) Combining colchicine with lipid-lowering drugs (statins and fibrates) can cause myopathy; (5) Several mechanisms have been implicated: competition for cytochrome P450 or P-glycoprotein, additive adverse effects (especially on muscle), and colchicine accumulation due to a reduction in its renal excretion; (6) Patients with gout should use colchicine only after failure of symptomatic treatment: ice application, paracetamol, and possibly ibuprofen, a nonsteroidal antiinflammatory drug with well-documented adverse effects; (7) If colchicine is nevertheless used, it should be at the minimum effective dose. Close clinical monitoring is required in order to detect early signs of adverse effects, especially diarrhoea, the earliest sign in patients with renal failure and in the elderly.

[Effectiveness of cardiometabolic risk reduction in patients with type 1 diabetes mellitus]. / A kardiometabolikus kockázati tényezôk kezelésének eredményessége 1-es típusú diabetesben szenvedôk körében.

UNLABELLED: The attainment and maintenance of therapeutic goal of cardiovascular risk factors are of great clinical importance. The effectiveness of cardiovascular risk management is not well characterized during regular care of patients with type 1 diabetes mellitus. AIM: The aim of the study was to estimate the effectiveness of cardiovascular risk management in type 1 diabetic patients. METHODS: Adult patients with type 1 diabetes mellitus (n = 533; 256 men, 277 women; age: 35.6 +/- 11.6 years; duration of diabetes: 18.0 +/- 11.1 years; x +/- SD) were consecutively enrolled from 11 diabetes outpatient departments. Data on medical history, actual treatment, anthropometric and laboratory parameters as well as actual blood pressure were registered, while eating and smoking habits, education level and physical activity were evaluated by standardized questionnaires. The treating goal was set according to the national guideline which corresponds to the current international task force. RESULTS: Of 533 patients, the body mass index target level (< 25 kg/m 2 ) was achieved by 295 (55.5%) patients. Ideal waist circumference (< 80 cm for women and < 94 cm for men) was measured in 140 (50.5%) and in 165 (63.7%) patients, respectively. Optimal glycaemic control (HbA 1c level < 6.5%) was documented in 45 (8.4%) patients. Lipid lowering drugs (statins, fibrates or ezetimibe) were used by 130 patients, among which 53.1% reached the target triglyceride level, 71.5% the target HDL-cholesterol and 27.8% the target LDL-cholesterol levels. Taking the lipid target values together, only 23 (17.7%) patients were at goal. Antihypertensive drugs were used by 173 patients among which 29.5% reached the systolic and 34.8% the diastolic target values (< 130/80 mmHg). Regarding smoking habits, 94 (17.7%) patients were current smokers and 102 (19.2%) ex-smokers. CONCLUSIONS: The attainment of therapeutic goal of cardiovascular risk factors proved to be difficult in a substantial part of patients. Further efforts are needed for attaining and maintaining the established goal of cardiovascular risk management during regular care of adult patients with type 1 diabetes mellitus.

Clofibric acid, a peroxisome proliferator-activated receptor alpha ligand, inhibits growth of human ovarian cancer.

Recent reports have shown that peroxisome proliferator-activated receptor (PPAR)alpha ligands reduce growth of some types of malignant tumors and prevent carcinogenesis. In this study, we investigated the inhibitory effect of clofibric acid (CA), a ligand for PPARalpha on growth of ovarian malignancy, in in vivo and in vitro experiments using OVCAR-3 and DISS cells derived from human ovarian cancer and aimed to elucidate the molecular mechanism of its antitumor effect. CA treatment significantly suppressed the growth of OVCAR-3 tumors xenotransplanted s.c. and significantly prolonged the survival of mice with malignant ascites derived from DISS cells as compared with control. CA also dose-dependently inhibited cell proliferation of cultured cell lines. CA treatment increased the expression of carbonyl reductase (CR), which promotes the conversion of prostaglandin E(2) (PGE(2)) to PGF(2alpha), in implanted OVCAR-3 tumors as well as cultured cells. CA treatment decreased PGE(2) level as well as vascular endothelial growth factor (VEGF) amount in both of OVCAR-3-tumor and DISS-derived ascites. Reduced microvessel density and induced apoptosis were found in solid OVCAR-3 tumors treated by CA. Transfection of CR expression vector into mouse ovarian cancer cells showed significant reduction of PGE(2) level as well as VEGF expression. These results indicate that CA produces potent antitumor effects against ovarian cancer in conjunction with a reduction of angiogenesis and induction of apoptosis. We conclude that CA could be an effective agent in ovarian cancer and should be tested alone and in combination with other anticancer drugs.

[Analysis of dietary habits and dietary intake in hypertensive smokers]. / Ocena zwyczajów zywieniowych i sposobu zywienia osób palacych papierosy z nadcisnieniem tetniczym.

The aim of this study was to compare dietary habits and nutrient intake of hypertensive smokers with hypertensive non-smokers. The study population comprised 30 hypertensive smokers and 35 non-smokers, aged 30-60y. The participants were subjected to a triple 24-h diet recall and to a dietary habits questionnaire. The results showed that smokers had unhealthy patterns of nutrient intake. Smokers declared consuming too much fat, cholesterol and too low antioxidant vitamins, calcium and fibre. It was found that concentration of vitamin E in smokers' daily diet is significant lower than in non-smokers. Smokers consumed significantly higher saturated fatty acids comparing to non-smokers. In conclusion, smokers have unhealthy diet and it may intensify harmful effects of smoking in their organism.

Is it necessary to add fibrate to statin therapy in the management of dyslipidemia of metabolic syndrome?

The available data have suggested a significant association between hypertriglyceridemia and cardiovascular disease. Although atherogenic dyslipidemia in patients with metabolic syndrome is characterized by high triglyceride, low HDL cholesterol and near normal LDL cholesterol levels, lowering LDL cholesterol is the first priority in treating dyslipidemia in patients with metabolic syndrome. The use of statins as monotherapy is still leaving some of these patients with mixed atherogenic dyslipidemia at high risk for coronary events. So, it seems beneficial to add a fibrate to statin therapy in the management of dyslipidemia of metabolic syndrome, especially in patients with inadequately corrected triglyceride levels with statin monotherapy.

Prolonged statin administration does not act on the cell-mediated immunity of HIV-infected dyslipidemic patients treated with a steady and effective highly active antiretroviral therapy. A two-year prospective study of statin versus fibrate administration.

OBJECTIVE: To assess whether statin administration for HIV-associated hyperlipidemia has long-term effects on immune recovery (as expressed by the trend of mean CD4+ lymphocyte count), in patients on a virologically-active HAART regimen since 12 months or more. METHODS: Single-centre, open-label, prospective study of 301 hyperlipidemic patients treated with statins (99 cases, with a predominant hypercholesterolemia), fibrates (116 subjects, when hypertriglyceridemia prevailed), or a isolated dietary/exercise program (86 patients, used as a control group). Neither epidemiological nor clinical, virological, or immunological differences were detected among the three study groups at baseline. During the subsequent follow-up, patients were excluded from evaluation should virological efficacy was not maintained, and/or initial hypolipidemic therapy was modified or interrupted for any reason. RESULTS: The quarterly assessment of mean CD4+ lymphocyte count did not disclose any statistically significant difference among the three study groups, since baseline and until at least 24 consecutive months of follow-up. Our data tend to exclude relevant in vivo negative activities of statins on immune system recovery of HIV-infected individuals who undergo a virologically effective HAART treatment. CONCLUSIONS: Multiple, pleiotropic features have been attributed to both statins and fibrates, and also apparently significant effects on laboratory markers of HIV disease progression have been recently claimed or expected. Despite some preliminary in vitro and ex-vivo models, both the main hypolipidemic classes administered for the management of HIV-related dyslipidemia (both statins and fibrates) do not seem to act significantly on clinical immune response of patients successfully treated with HAART. Multifactorial pathways are expected to interact with the cell-mediated immune system of HIV-infected patients undergoing successful HAART, and further studies are needed to elucidate whether more subtle immune effects might be prompted by a long-term administration of hypolipidemic drugs in this speciasl setting.

Effects of ciprofibrate on testicular and adrenal steroidogenic enzymes in the rat.

Testicular and adrenal steroidogenic enzymes were measured radiometrically following oral dosing of rats with ciprofibrate (2-[4-(2,2-dichlorocyclopropyl) phenoxyl]-2-methylpropinoic acid), a peroxisome proliferator. Six-week-old male Fisher 344 rats were fed a diet containing ciprofibrate (0.025%, w/w) for 3, 7, 14, 28, 56, 84, 112 or 140 days leading to a daily ciprofibrate intake of approximately 15 mg/kg body weight/day. Ciprofibrate caused a marked inhibition of testicular 3beta-hydroxysteroid dehydrogenase-isomerase (3beta-HSD) activity that was significant after 3 days and subsequently decreased to 40% of control level. Ciprofibrate treatment also reduced 17beta-hydroxysteroid dehydrogenase (17beta-HSD) activity to a lesser extent but had no effect on 17-hydroxylase (17-OHase) activity. Immunoblot analyses indicated that ciprofibrate treatment did not alter enzyme protein levels and semi-quantitative RT-PCR analysis also revealed no significant changes in testicular 3beta-HSD mRNA levels. Furthermore, in addition to the enzyme-specific effect of ciprofibrate on 3beta-HSD in the testes, a tissue-specific effect was also evident, since no significant effects of ciprofibrate were seen on the activities of 3beta-HSD or 21-OHase in the adrenal glands from the same animals.

Reduction of beta-oxidation capacity of rat liver mitochondria by feeding orotic acid.

Rats were maintained on fat-free high carbohydrate diets either with or without orotic acid (1%, w/w), pantethine (1%, w/w), adenine (0.25%, w/w), and/or p-chlorophenoxyisobutyrate (0.25%, w/w). Oxidation of fatty acid by liver mitochondria was inhibited to less than half that of the control after administration of orotic acid. Activities of acyl-CoA dehydrogenases were markedly decreased by orotic acid administration, but the following enzyme activities were not, or only slightly decreased: acyl-CoA synthetase, carnitine acyltransferases, enoyl-CoA hydratase, 3-hydroxyacyl-CoA dehydrogenase and 3-ketoacyl-CoA thiolase. Simultaneous addition of pantethine in the orotic acid-containing diet prevented induction of fatty liver. It also prevented decreases in fatty acid oxidation capacity and acyl-CoA dehydrogenase activity. Introduction of adenine or p-chlorophenoxyisobutyrate, which reverse orotic acid-induced fatty liver, reversed oxidation and acyl-CoA dehydrogenase activities to control levels. The oxidation capacity of the peroxisomal system remained unchanged after administration of orotic acid.

Studies with etofibrate in the rat. Part II: A comparison of the effects of prolonged and acute administration on plasma lipids, liver enzymes and adipose tissue lipolysis.

To contribute to the understanding of the hypolipidemic action of etofibrate, which is the 1,2-ethandiol ester of clofibric acid and nicotinic acid, 300 mg of this drug/kg body weight or of the medium were administered daily by a stomach tube to normolipidemic rats. Some animals were decapitated at the 10th day of daily treatment (prolonged treatment), whereas others were studied at different times after one single administration (acute treatment). In animals on prolonged treatment etofibrate decreased plasma levels of cholesterol, triacylglycerols, free fatty acids (FFA) and glycerol, as well as the total and unesterified cholesterol concentrations, in liver microsomes. In these rats, etofibrate increased the activity of liver cytosolic glycerol-3-P dehydrogenase, whereas it decreased the activity of both microsomal HMG-CoA reductase and cholesterol 7 alpha-hydroxylase and did not affect acyl-CoA: cholesterol acyltransferase (ACAT). At 3, 5 and 7 h after acute treatment, etofibrate decreased plasma levels of triacylglycerols, glycerol and FFA, and this effect disappeared at 24 h, whereas plasma cholesterol did not change 3 h after etofibrate but decreased at 5 and 7 h and remained low after 24 h, and a similar change was found in the liver microsomes free cholesterol concentration. However, with the exception of a significant reduction in cytosolic glycerol-3-P dehydrogenase at 7 h and in ACAT at 5 h, acute etofibrate treatment did not affect the activity of the liver enzymes studied. At low concentrations (10(-5) M) in the incubation medium, etofibrate decreased the release of both FFA and glycerol by epididymal fat pad pieces incubated in vitro. These findings together with those previously reported by us in rats using a similar etofibrate treatment protocol [6] indicate that etofibrate decreases the availability of lipolytic products in the liver by acting on their release from adipose tissue and on their intrinsic hepatic metabolism. Consequently, this drug would decrease liver VLDL triacylglycerol synthesis and secretion, which together with facilitating the clearance of circulating triacylglycerols causes its hypotriglyceridemic effect. The hypocholesterolemic effect of etofibrate after acute treatment may be a secondary consequence of the reduced liver VLDL production caused by decreased adipose tissue lipolysis, but after prolonged treatment, this effect also seems to be influenced by the inhibition of HMG-CoA reductase activity which would reduce cholesterol synthesis.

Coordinate induction of acyl-CoA binding protein, fatty acid binding protein and peroxisomal beta-oxidation by peroxisome proliferators.

Acyl-CoA binding protein (ACBP) and fatty acid binding protein (FABP) are important intracellular lipid binding proteins. The purpose of the present experiments was to test the hypothesis that peroxisome proliferators induce ACBP in rat hepatocytes as has been shown previously for FABP. The effects of two structurally dissimilar peroxisome proliferators perfluorodecanoic acid (PFDA) and clofibric acid (CPIB) were examined in primary rat hepatocyte cultures in a chemically defined media. Both compounds alter lipid metabolism in primary rat hepatocytes in a similar fashion, although PFDA is more potent than CPIB at inducing peroxisomal beta-oxidation. In addition, PFDA and CPIB compete with long-chain fatty acids for binding to FABP but do not compete with long-chain acyl-CoA esters for binding to ACBP. The concentration of ACBP and FABP was increased in peroxisome proliferator-treated hepatocytes relative to vehicle controls within 48 h of treatment. Evidence is given to support increases in ACBP and FABP mRNA being the cause of the increased protein levels by peroxisome proliferators. In addition, the peroxisome proliferators PFDA, perfluorooctanoic acid and ciprofibrate induced hepatic ACBP following in vivo administration to rats indicating that this phenomena is not exclusive to in vitro systems. Therefore, ACBP appears to be a member of the peroxisome proliferator loci, a group of lipid metabolizing proteins, including FABP, which are regulated by peroxisome proliferators such as fibric acids and perfluorinated fatty acids.

Mechanism of block of single protopores of the Torpedo chloride channel ClC-0 by 2-(p-chlorophenoxy)butyric acid (CPB).

We investigated in detail the mechanism of inhibition by the S(-) enantiomer of 2-(p-chlorophenoxy)butyric acid (CPB) of the Torpedo Cl(-)channel, ClC-0. The substance has been previously shown to inhibit the homologous skeletal muscle channel, CLC-1. ClC-0 is a homodimer with probably two independently gated protopores that are conductive only if an additional common gate is open. As a simplification, we used a mutant of ClC-0 (C212S) that has the common gate "locked open" (Lin, Y.W., C.W. Lin, and T.Y. Chen. 1999. J. Gen. Physiol. 114:1-12). CPB inhibits C212S currents only when applied to the cytoplasmic side, and single-channel recordings at voltages (V) between -120 and -80 mV demonstrate that it acts independently on individual protopores by introducing a long-lived nonconductive state with no effect on the conductance and little effect on the lifetime of the open state. Steady-state macroscopic currents at -140 mV are half-inhibited by approximately 0.5 mM CPB, but the inhibition decreases with V and vanishes for V > or = 40 mV. Relaxations of CPB inhibition after voltage steps are seen in the current responses as an additional exponential component that is much slower than the gating of drug-free protopores. For V = 60 mV) with an IC50 of approximately 30-40 mM. Altogether, these findings support a model for the mechanism of CPB inhibition in which the drug competes with Cl(-) for binding to a site of the pore where it blocks permeation. CPB binds preferentially to closed channels, and thereby also strongly alters the gating of the single protopore. Since the affinity of CPB for open WT pores is extremely low, we cannot decide in this case if it acts also as an open pore blocker. However, the experiments with the mutant K519E strongly support this interpretation. CPB block may become a useful tool to study the pore of ClC channels. As a first application, our results provide additional evidence for a double-barreled structure of ClC-0 and ClC-1.

Pharmacokinetic interactions between statins and fibrates.

Concomitant use of a fibrate and a statin may offer a therapeutic advantage to patients with dyslipidemia, especially in patients whose low-density lipoprotein cholesterol is controlled by statins but whose high-density lipoprotein cholesterol or triglycerides, or both, are not within goal. However, concern about drug-drug interactions may preclude optimal use of combination statin-fibrate therapy. This article reviews the pharmacokinetics between statins and fibrates, addressing risks associated with drug-drug interactions and combination therapy.

Modifying plasma low-density lipoprotein and high-density lipoprotein cholesterol: what combinations are available in the future?

Despite a growing body of research on the benefit of combination drug therapy for dyslipidemia in the metabolic syndrome or diabetes mellitus, there are insufficient outcome data on the use of combination therapy as well as inadequate data to compare certain combination regimens. The focus of the therapeutic approach in treating the metabolic syndrome has been almost exclusively on low-density lipoprotein (LDL) cholesterol for approximately the past 10 years, and specifically on statin therapy. Although results of epidemiologic studies as well as clinical trials using angiographic and clinical end points confirm the association of LDL cholesterol and risk of coronary artery disease, data are lacking regarding the effects of combination therapy in the management of coronary artery disease. Management of the metabolic syndrome focusing on the modification of plasma LDL as well as high-density lipoprotein cholesterol is reviewed. Future management strategies with the use of novel combination therapy is also discussed.